CN104109182A - Preparation method of gemcitabine hydrochloride - Google Patents
Preparation method of gemcitabine hydrochloride Download PDFInfo
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- CN104109182A CN104109182A CN201310132357.0A CN201310132357A CN104109182A CN 104109182 A CN104109182 A CN 104109182A CN 201310132357 A CN201310132357 A CN 201310132357A CN 104109182 A CN104109182 A CN 104109182A
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 23
- 229960005144 gemcitabine hydrochloride Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 21
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 claims description 20
- 238000010189 synthetic method Methods 0.000 claims description 15
- 238000006722 reduction reaction Methods 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- 239000007810 chemical reaction solvent Substances 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 238000010009 beating Methods 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- 229940104302 cytosine Drugs 0.000 claims description 5
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 5
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 claims description 4
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 claims description 4
- 229940094989 trimethylsilane Drugs 0.000 claims description 4
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 3
- HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 229960005277 gemcitabine Drugs 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 239000004575 stone Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 4
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
- 238000005694 sulfonylation reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 13
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 0 C[C@](CC[C@@](COC(C1C=CC=CC1)=O)*1)C1C(C*)O Chemical compound C[C@](CC[C@@](COC(C1C=CC=CC1)=O)*1)C1C(C*)O 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- -1 compound gemcitabine hydrochloride Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- RFFPAVPLLZAQTB-BXXZVTAOSA-N (2r,3r,4r)-2,3,4,5-tetrahydroxypentanoyl fluoride Chemical class OC[C@@H](O)[C@@H](O)[C@@H](O)C(F)=O RFFPAVPLLZAQTB-BXXZVTAOSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OITXRQPRVXRGLL-UHFFFAOYSA-N C=[O]=C(C1=CC=CCC1)O Chemical compound C=[O]=C(C1=CC=CCC1)O OITXRQPRVXRGLL-UHFFFAOYSA-N 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Abstract
The invention belongs to the drug synthesis field, and provides a novel method for synthesizing gemcitabine hydrochloride. In the method, 2-deoxy-2,2-difluoro-D-erythro-pentafuranous-one-3,5-dibenzoate (bifluoro-sugar for short) is taken as the primary raw material, and then the primary raw material is subjected to steps of reduction, methyl-sulfonylation, condensation, deprotection, salt forming, separation, and refinement so as to obtain the finished product. The method has the advantages of simple technology, high yield, high purity (which can reach 99.8% or more), and more suitability for industrial production.
Description
Technical field
The invention belongs to the synthetic field of medicine, refer more particularly to a kind of synthetic method of antineoplastic compound gemcitabine hydrochloride.
Background technology
Gemcitabine hydrochloride is nucleosides homologue, belongs to cell cycle specific antitumour drug.The gemcitabine hydrochloride of U.S. FDA approval Liao Lilai company in 1996 production is as the first-line drug for the treatment of carcinoma of the pancreas, and approval in 1998 is as treatment nonsmall-cell lung cancer.This medicine is applicable to treat inoperable late period or transitivity carcinoma of the pancreas and treatment Local advancement or Metastatic Nsclc, treatment Advanced non-small cell lung cancer, nonsmall-cell lung cancer, carcinoma of the pancreas, bladder cancer, mammary cancer and other noumenal tumours.
Bibliographical information is also few about synthesizing of gemcitabine at present, related documents report mainly contains Hertel, L.W. wait J. Org.Chem, 1988,53 (11), 2406-2409 and Chou, T.S. wait Synthesis, 1992, (6), 565-70 and patent CN 1724553A and CN 1442420A etc.These methods are all from key intermediate 2-deoxidation-2, and the fluoro-D-RIBOSE derivative of 2-bis-starts, reduction, condensation, again through hydrolysis, isomer separation, the step such as refining, and main synthetic route is as follows:
Method one:
Method two:
Method three:
Described in method one, synthetic route is because its Process Route is comparatively reasonable, reaction conditions gentleness, and yield is better, is relatively suitable for commercial scale production, so, these routes that adopt in actual production at present more.Domestic a lot of pharmacy producer, completes the synthetic of gemcitabine hydrochloride such as Jiangsu Haosen Pharmaceutical Co., Ltd etc. all takes this synthetic route.
Our company is in to the process of above-mentioned operational path research, find that in prior art, there are the following problems: 1. in " two fluorine sugar " reduction step, take ether or tetrahydrofuran (THF) to serve as reduction solvent, these two kinds of solvent explosive and toxicity are large, and take methyl alcohol as cancellation solvent, increased solvent and used kind; 2. gained intermediate Gemzart-3 ' in condensation step, 5 '-dibenzoate intermediate (GE-3) purity is low, yield is low; 3. in deprotection steps, take the alkaline systems such as sodium methylate/methyl alcohol, ammonia hydroxide/methanol, sodium hydroxide/methyl alcohol, deprotection is incomplete and yield is low; 4. split treating process products obtained therefrom purity low, do not reach USP standard.
For the problems referred to above of prior art, the present invention proposes the preparation method of the gemcitabine hydrochloride that a kind of reactions steps is simple, aftertreatment purifying is easy, be more suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to the problem existing in existing gemcitabine hydrochloride synthetic method, proposed that a kind of reactions steps is simple, aftertreatment purifying is easy, purity is high, be more suitable for the preparation method of the gemcitabine hydrochloride of suitability for industrialized production.
To achieve these goals, the present invention adopts following technical scheme:
1, a synthetic method for gemcitabine hydrochloride, is characterized in that comprising the steps:
(1) taking " two fluorine sugar " (GE-0) as starting raw material, select three tert.-butoxy lithium aluminium hydride be reductive agent, ethyl acetate is served as reaction solvent generation reduction reaction:
(2) 2-deoxidation-2, fluoro-D-RIBOSE-3 of 2-bis-, 5-dibenzoate (GE-1) reacts with Methanesulfonyl chloride generation methylsulfonyl:
(3) 2-deoxidation-2, fluoro-D-RIBOSE-3 of 2-bis-, 5-dibenzoate-1-methanesulfonate ester (GE-2) and N, two (trimethyl silane) cytosine(Cyt) generation condensation reactions of O-:
(4) Gemzart-3 ', there is deprotection reaction and obtain gemcitabine hydrochloride crude product in 5 '-dibenzoate intermediate (GE-3):
(5) pull an oar by thermal backflow and recrystallization method splits gemcitabine hydrochloride crude product and refining:
2, a kind of synthetic method as claimed in claim 1, it is characterized in that in step (1), described reductive agent is three tert.-butoxy lithium aluminium hydride, reduction solvent is ethyl acetate, and the ingenious selective reduction that utilizes three tert.-butoxy lithium aluminium hydride of the inventive method is carried out selective reduction to the carbonyl on " two fluorine sugar " ribose, and ethyl acetate is not had to reductibility, and ethyl acetate had both been served as reaction solvent, serve as again the extraction solvent of aftertreatment, kill two birds with one stone.
3, a synthetic method as claimed in claim 1, is characterized in that the methylsulfonylization reaction in step (2), and preferably methylene dichloride serves as reaction solvent, and triethylamine serves as acid binding agent.
4, a synthetic method as claimed in claim 1, is characterized in that the condensation reaction solvent in step (3) is methyl-phenoxide, reacts the concentrated gained crude product of complete extraction and carries out purification process through sodium bicarbonate aqueous solution/ethanol, ethanol making beating respectively.
5, a kind of synthetic method as claimed in claim 1; it is characterized in that the Deprotection in step (4) carries out in TERTIARY BUTYL AMINE/methanol system; reacting the concentrated gained gemcitabine crude product salify of complete extraction is to carry out in concentrated hydrochloric acid, preferably, also adds ethanol.
6, a synthetic method as claimed in claim 1, is characterized in that preferably 95% ethanol of resolution solvent in step (5), in recrystallization solvent preferred alcohol-water mixed solvent, carries out.
Compared with prior art, the present invention has following beneficial effect: 1. the present invention is preparing intermediate 2-deoxidation-2, fluoro-D-RIBOSE-3 of 2-bis-, in the step of 5-dibenzoate (GE-1), the ethyl acetate of taking of novelty is served as reaction solvent, taking " two fluorine sugar " (GE-0) as starting raw material, selecting three tert.-butoxy lithium aluminium hydride is reductive agent, ethyl acetate is served as reaction solvent, the ingenious selective reduction that utilizes three tert.-butoxy lithium aluminium hydride, carbonyl on GE-0 ribose is carried out to selective reduction, and ethyl acetate is not had to reductibility, and ethyl acetate had both been served as reaction solvent, serve as again the extraction solvent of aftertreatment, kill two birds with one stone, 2. condensation reaction takes methyl-phenoxide to serve as reaction solvent, in extraction process, add ethyl acetate, extracting operation is carried out in the two mixing, react the concentrated gained crude product of complete extraction and carry out purification process through sodium bicarbonate aqueous solution/ethanol, ethanol making beating respectively, utilize the 2 '-deoxidation-2 ' of the method gained intermediate, 2 '-difluoro cytidine-3 ', 5 '-dibenzoate intermediate (GE-3) purity and yield are all higher, and are conducive to the carrying out of subsequent step, 3. in deprotection reaction, novelty take TERTIARY BUTYL AMINE/methanol system, deprotection reaction is complete, 4. split in treating process, first take 95% alcohol heat reflux making beating, then take ethanol-water mixed system recrystallization, obtain smoothly purity higher than 99.8% gemcitabine hydrochloride product.
Your simple synthetic method of gemcitabine hydrochloride of the present invention is easily controlled, post-processing operation is simple, purity is high, be more conducive to suitability for industrialized production, and the raw material that uses is domestic all a supply, environmental pollution is little, raw material is cheap and easy to get.Therefore the novel method of preparing gemcitabine hydrochloride provided by the invention has wide commercial application prospect.
Embodiment
For a better understanding of the present invention, below in conjunction with embodiment, the present invention is further described in detail.
embodiment 1
500g GE-0 is added in 5L there-necked flask, then add 2.5L ethyl acetate, under 0-10 DEG C of mechanical stirring, add gradually three tert.-butoxy lithium aluminium hydride 500g (while feeding in raw material, temperature of reaction does not exceed 10 DEG C) in batches, about 1-2 h is reinforced complete, then continues reaction 4 hours in 0-10 DEG C.TLC monitors reaction end, after completion of the reaction, under 0-10 DEG C of mechanical stirring, dropwise add concentrated hydrochloric acid 200 ml(reacting liquid temperatures not exceed 10 DEG C), after dropwising, suction filtration, filter cake washs with 1.5L*3, and merging filtrate, with twice of saturated aqueous common salt 2L*2 washing, separate ethyl acetate layer, concentrated organic layer, to dry, obtains light yellow oil 475g, and yield is 94.5%.
embodiment 2
475g GE-1 is added in 5L there-necked flask, then add in 2.5L methylene dichloride, subcooling recycle pump is cooled to 5-10 DEG C, under mechanical stirring, add 261ml triethylamine, under 0-10 DEG C of mechanical stirring, dropwise add 117ml Methanesulfonyl chloride, about 1-2 hour reinforced complete, then continues reaction 4 hours in 5-10 DEG C.After completion of the reaction, with 1mol/L aqueous hydrochloric acid 2L, 5% sodium bicarbonate aqueous solution 2L, hao water 2L washing, concentrated organic layer, to dry, obtains sundown oily matter (placing crystallize out after 1-2 days) 566g respectively, and yield is 98.8%.
embodiment 3
275g cytosine(Cyt) and 0.5g ammonium sulfate are added in reaction flask, then add 1.65L hexamethyldisilane amine, be heated to reflux (120-130 DEG C), after reaction solution clarification, continue to stir 2 hours, be cooled to room temperature, suction filtration, filter cake vacuum-drying obtains 605g N, two (trimethyl silane) cytosine(Cyt)s of O-, yield is 95%.
By upper 565g N, two (trimethyl silane) cytosine(Cyt)s of O-add in 5L there-necked flask, then add 1.15L methyl-phenoxide, after stirring, then add 1.15L trifluoromethanesulfonic acid trimethylsilyl group, be heated to 125 DEG C of left and right, reaction solution is dissolved in 565g GE-2 in 1.15L methyl-phenoxide, and dropwise adds in reaction solution after all dissolving, about 1-2 h dropwises, and then under reflux conditions, continues reaction 5 hours.After completion of the reaction, add 2.3L ethyl acetate, 100L purified water extraction 2 times, organic layer is concentrated into dry, obtain the thick material of burgundy, then add 1.4L ethanol, after stirring, add gradually 1.4L10% sodium bicarbonate aqueous solution vigorous stirring 0.5h, suction filtration, filter cake adds the making beating of 2.8L ethanol, stirs suction filtration after 0.5 hour, be dried to obtain the about 439g of pale solid, yield is 78.9%.
embodiment 4
439g GE-3 is added in 5L there-necked flask, then add 2.2L methyl alcohol, after stirring, under room temperature condition, then add gradually 248ml TERTIARY BUTYL AMINE, after dropwising, continue room temperature reaction 18 hours.After completion of the reaction, concentration of reaction solution, to dry, obtains thick dark brown yellow oil, add after 1.5L water stirring and dissolving, add 1.5L ethyl acetate, extraction, retains water layer, twice of 1.5L for water layer × 2 ethyl acetate washing, retain water, add 43.9g gac, 80 DEG C are stirred 1 hour, heat filtering, concentrated water is to dry.In gained resistates, add 1.3L ethanol, return stirring until be uniformly dissolved, dropwise adds concentrated hydrochloric acid to adjust pH to 2 left and right, and return stirring 1 hour, is cooled to room temperature, suction filtration, and filtration cakes torrefaction, obtains gemcitabine hydrochloride crude product 119g, and yield is 55.3%.
embodiment 5
Above-mentioned gemcitabine hydrochloride crude product 119g is added in reaction flask, then add 1.78L 95% ethanol, be warming up to return stirring 1 hour, heat filtering, obtains white solid 58.5g;
Add 585ml 95% ethanol to be warming up to return stirring 1 hour 58.5g the said products, heat filtering, obtains white solid 54g;
54g the said products is added to 270ml ethanol, after stirring, add 162ml purified water, be back to dissolving, add 10g gac, return stirring 1 hour, heat filtering, cooling filtrate is to room temperature, filter, obtain white solid 30.8g, purity is greater than 99.8%, and yield is 25.9%.
Claims (6)
1. a synthetic method for gemcitabine hydrochloride, is characterized in that comprising the steps:
1) taking " two fluorine sugar " (GE-0) as starting raw material, select three tert.-butoxy lithium aluminium hydride be reductive agent, ethyl acetate is served as reaction solvent generation reduction reaction:
2) 2-deoxidation-2, fluoro-D-RIBOSE-3 of 2-bis-, 5-dibenzoate (GE-1) reacts with Methanesulfonyl chloride generation methylsulfonyl:
3) 2-deoxidation-2, fluoro-D-RIBOSE-3 of 2-bis-, 5-dibenzoate-1-methanesulfonate ester (GE-2) and N, two (trimethyl silane) cytosine(Cyt) generation condensation reactions of O-:
4) Gemzart-3 ', there is deprotection reaction and obtain gemcitabine hydrochloride crude product in 5 '-dibenzoate intermediate (GE-3):
5) pull an oar by thermal backflow and recrystallization method splits gemcitabine hydrochloride crude product and refining.
2. a synthetic method as claimed in claim 1, it is characterized in that in step (1), described reductive agent is three tert.-butoxy lithium aluminium hydride, reduction solvent is ethyl acetate, and the ingenious selective reduction that utilizes three tert.-butoxy lithium aluminium hydride of the inventive method is carried out selective reduction to the carbonyl on " two fluorine sugar " ribose, and ethyl acetate is not had to reductibility, and ethyl acetate had both been served as reaction solvent, serve as again the extraction solvent of aftertreatment, kill two birds with one stone.
3. a synthetic method as claimed in claim 1, is characterized in that the methylsulfonylization reaction in step (2), and preferably methylene dichloride serves as reaction solvent, and triethylamine serves as acid binding agent.
4. a synthetic method as claimed in claim 1, is characterized in that the condensation reaction solvent in step (3) is methyl-phenoxide, reacts the concentrated gained crude product of complete extraction and carries out purification process through sodium bicarbonate aqueous solution/ethanol, ethanol making beating respectively.
5. a synthetic method as claimed in claim 1; it is characterized in that the Deprotection in step (4) carries out in TERTIARY BUTYL AMINE/methanol system; reacting the concentrated gained gemcitabine crude product salify of complete extraction is to carry out in concentrated hydrochloric acid, preferably, also adds ethanol.
6. a synthetic method as claimed in claim 1, is characterized in that preferably 95% ethanol of resolution solvent in step (5), in recrystallization solvent preferred alcohol-water mixed solvent, carries out.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106905398A (en) * | 2017-01-25 | 2017-06-30 | 浙江农林大学 | A kind of synthetic method of Suo Feibuwei |
| CN109651459A (en) * | 2019-01-24 | 2019-04-19 | 江苏八巨药业有限公司 | A kind of preparation method of gemcitabine intermediate methylsulfonyl ester |
| CN112079891A (en) * | 2020-09-17 | 2020-12-15 | 苏州华鑫医药科技有限公司 | Preparation method of antitumor drug gemcitabine hydrochloride |
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|---|---|---|---|---|
| US20100105887A1 (en) * | 2008-10-23 | 2010-04-29 | Prime European Therapeuticals S.P.A. | Process for the preparation of gemcitabine hydrochloride |
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| CN106905398A (en) * | 2017-01-25 | 2017-06-30 | 浙江农林大学 | A kind of synthetic method of Suo Feibuwei |
| CN106905398B (en) * | 2017-01-25 | 2019-12-10 | 浙江农林大学 | Synthetic method of sofosbuvir |
| CN109651459A (en) * | 2019-01-24 | 2019-04-19 | 江苏八巨药业有限公司 | A kind of preparation method of gemcitabine intermediate methylsulfonyl ester |
| CN109651459B (en) * | 2019-01-24 | 2020-09-08 | 江苏八巨药业有限公司 | Preparation method of gemcitabine intermediate methanesulfonyl ester |
| CN112079891A (en) * | 2020-09-17 | 2020-12-15 | 苏州华鑫医药科技有限公司 | Preparation method of antitumor drug gemcitabine hydrochloride |
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